Immunologic Role of Extracellular Vesicles and Exosomes in the Pathogenesis of Cystic Fibrosis.

Cystic Fibrosis (CF) is the most common lethal autosomal recessive disease that affects many organs including, lung, pancreas and liver. Cystic fibrosis is a monogenic disease and occurs in the white Caucasians. Massive neutrophil granulocyte influx in the airways is one of the characteristics of CF. Extracellular Vesicles (EVs), microvesicles, and exosomes are vesicles released from cells into extracellular space of the body and are able to influence other cells by different methods. They have an important role in the intracellular communication by transferring information between donor and recipients cells. Granulocytes are known as the main source of microparticles in the CF patients. Microparticles derived from neutrophils are associated with the extensive neutrophil influx into airways and aggregation at the epithelial surface of the CF patient's respiratory tract. Exosomes are found in almost all body fluids, such as urine, sputum, Bronchoalveolar Lavage (BAL), milk, Cerebrospinal Fluid (CSF), plasma and sputum. Examination of exosomes derived from CF patients may be helpful in the characterization of pathogenesis of disease in detail. In this mini review, we have summarized the role of microparticles and exosomes in pathogenesis of CF and finally discussed the feasibility of this particle in treatment approaches.


INTRODUCTION
Biological markers or biomarkers generally indicate the biological status, health or pathological conditions, or conditions for assessment of treatment response.
Biomarkers can be used as a safe way to identify pathological conditions in various diseases, including respiratory diseases. Extracellular vesicles (EVs) and exosomes are small plasmid mucous membranes (40-150 nm) that are released from cells such as macrophages, endothelial cells, granulocytes, monocytes and lymphocytes during chemical and physical stimulation and apoptosis and are referred to as biomarkers (1,2).
Exosomes are found in almost all body fluids, such as urine, sputum, Bronchoalveolar Lavage (BAL), milk, Cerebrospinal Fluid (CSF) and plasma (3,4). It contains proteins and lipids that may help in understanding its characteristics, and may represent the main source of the cells and the type of stimulation that caused its formation (5)(6)(7).
Exosomal lipids are mainly cholesterol, phospholipid, phosphatidylserine, and prostaglandin-free nuclei, mitochondrial and ribosomal proteins (8,9)  have an important role in the biology of lung function as an intercellular interface in the respiratory system (12).
Besides, exosomes control the inflammation signaling through intracellular communication and as a part of response to stress, may also play a role in the respiratory tract (13,14). In this short review paper, the possible role of exosomes in the pathogenesis of cystic fibrosis has been reviewed in detail.

Cystic fibrosis and pathogenesis
CF is defined as an autosomal recessive respiratory genetic disease induced by mutations in the Cystic Fibrosis Transmembrane conductance Regulator CFTR gene, which encodes important protein in body (15). This mutation disrupts the activity of the chlorine channel and eventually causes the neutrophil influx into the airway (16), ( Figure 1).
Dysfunction of chloride channel in CF patient that eventually causes neutrophil influx into the airway of CF patients. Since the early detection of the CFTR gene mutation, 1500 different mutations have been identified for CFTR. ∆F 508 is the most common type of mutation in CF patients which is due to the deletion of phenylalanine in position 508, and is found in 66% of CF patients (14). Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) are the most common bacteria which affect CF patients (22). Emerging observations indicated that CFTR acts as a receptor for P.
aeruginosa and causes intracellular uptake and bacterial destruction (23). S. aureus and P. aeruginosa are mainly located on the mucus layer of the epithelial cell in the respiratory system (24,25).
Dehydration of airway surface liquid is the main cause of impaired cilia functioning and mucociliary clearance in CF patient, and in a way causes inhaled bacteria not to be cleared from the airways (26,27).
Due to lower levels of oxygen in sputum of CF patient, P. aeruginosa can be transformed from non-mucoid to mucoid state in the respiratory system (26). Exosomes (less than 150 nm) are vesicles that are released to the extracellular environment. Recent data show that exosomes are an alternative way of eliminating waste products in order to maintain cellular homeostasis (4,(42)(43)(44)(45) and were shown to have immune regulatory effects (46,47) .  It has been shown that microparticles are derived from CF granulocytes that are associated with extensive entry of neutrophils into airways and aggregation at the epithelial surface of the respiratory tract in CF patients (51).
Microparticles cause persistence of inflammation and play a role in the pre-inflammatory response of CF patients   Besides, blocking microparticles such as exosomes may exacerbate the disease and promote immunity-enhancing induced by particles, and could be considered as a suggestive approach to treat CF diseases.